It is well known that repeated administration of amphetamine or cocaine to animals results in increases in the motoric effects of such drugs. The precise mechanism underlying this phenomenon of behavioral sensitization are still not entirely understood. Alterations in mechanisms regulating dopamine release, alterations in post-synaptic DA receptors and decreases in somato dendritic autoreceptor sensitivity have all been advanced as possible causes. Pharmacokinetic factors may also pay a role. The purpose of these studies was directed at further elucidating the role of the latter variables. We have found that hyperactivity (D1 DA agpmost)induced by either + SKF 38393 or apomorphine injected into the n.accumbens was not modified by chronic cocaine pretreatment suggesting that neither D1 nor D2 DA receptor function had been altered. Although rats treated chronically with cocaine did show sensitization when challenged with cocaine intraperitoneally they failed to show sensitization when challenged with cocaine either intravenously (circumventing "first-pass" metabolism), intraventricularly, or focally into the n.accumbens. Sensitization was also not seen following challenges with intraven-tricular or intra-accumbens amphetamine or CFT (a cocaine analog). Brain levels of cocaine were found to be almost 100% higher 30 min after a challenge dose given 24 hours following termination of chronic treatment. These findings further support a critical role of pharmacokinetic factors in some aspects of cocaine-sensitization.